Proteomic Profiling in Predicting Response in Patients Receiving Erlotinib for Stage IIIB, Stage IV, or Recurrent Non-Small Cell Lung Cancer

A Feasibility Study Investigating Translational Science in Chemotherapy-Naive Patients With Stage IIIb or IV Non-Small Cell Lung Cancer (NSCLC) Treated With the EGFR-TKI, Erlotinib

RATIONALE: Studying samples of tumor tissue, blood, and urine in the laboratory from patients receiving erlotinib may help doctors predict how patients will respond to treatment.

PURPOSE: The phase II trial is studying proteomic profiling to see how well it predicts response in patients receiving erlotinib for stage IIIB, stage IV, or recurrent non-small cell lung cancer.

Study Overview

• Status: Completed
• Conditions: Lung Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: bevacizumab; Drug: carboplatin; Drug: erlotinib hydrochloride; Drug: paclitaxel; Genetic: gene expression analysis; Genetic: protein expression analysis; Genetic: proteomic profiling

Detailed Description

OBJECTIVES:

Primary

• To define a pre-treatment tumor proteomic profile that predicts response, stable disease, or progressive disease in patients with stage IIIB, stage IV, or recurrent non-small cell lung cancer treated with erlotinib hydrochloride.

Secondary

• To test and refine a pre-treatment serum proteomic expression pattern that predicts response to erlotinib hydrochloride and/or carboplatin and paclitaxel after failing treatment with erlotinib hydrochloride.
• To test and refine tumor proteomic profiles that predict response to carboplatin and paclitaxel after failing treatment with erlotinib hydrochloride.
• To analyze individual and pattern(s) of erlotinib hydrochloride-induced genomic and proteomic biomarker changes in relation to response or non-response to treatment.
• To correlate the efficacy and toxicity of erlotinib hydrochloride with expression of EGFR, EGFR pathway, ErbB family, and other related biomarkers.
• To determine a set of biomarkers to be evaluated in tumor tissue or surrogate tissues prior to treatment with erlotinib hydrochloride to enable patient selection for therapy.
• To estimate response rate and progression-free and overall survival of patients treated with erlotinib hydrochloride as initial therapy.
• To characterize the safety profile of erlotinib hydrochloride in these patients.

OUTLINE: This is a multicenter study.

Patients receive oral erlotinib hydrochloride once daily until disease progression.

At the time of disease progression, patients receive standard chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 15-30 minutes on day 1. Patients with non-squamous cell non-small cell lung cancer also receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses.

Tumor tissue, plasma, serum, and urine samples are collected at baseline for proteomics analysis.

After the completion of study treatment, patients are followed every 8 weeks.

• Study Type: Interventional
• Enrollment (Actual): 116
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Emory University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0942
      • University of Michigan Comprehensive Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt-Ingram Cancer Center
    • Nashville, Tennessee, United States, 37064
      • Vanderbilt-Ingram Cancer Center - Cool Springs
    • Nashville, Tennessee, United States, 37064
      • Vanderbilt-Ingram Cancer Center at Franklin
  • Texas
    • Houston, Texas, United States, 77030-4009
      • M. D. Anderson Cancer Center at University of Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed non-small cell lung cancer (NSCLC), meeting 1 of the following criteria:

  • Stage IIIB (with pleural effusion) or stage IV disease
  • Recurrent disease after prior surgery
• Measurable or evaluable disease is desirable but not required

• No untreated symptomatic brain metastases

  • Patients who are neurologically unstable despite radiotherapy for the brain metastases are not eligible
  • No requirement for steroids to control neurological symptoms

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• ANC ≥ 1,500/mm³
• Hemoglobin ≥ 9 g/dL
• Platelet count ≥ 100,000/mm³
• Creatinine ≤ 2.0 mg/dL
• Total bilirubin ≤ 1.5 mg/dL
• Normal hemostasis by history
• PT/PTT within 0.5 seconds of normal range
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Willing to undergo biopsy procedures
• No known severe hypersensitivity to erlotinib hydrochloride or any of the excipients of this product
• No other concurrent malignancies or malignancies diagnosed within the past 5 years, except basal cell carcinoma or cervical cancer in situ

• No significant cardiac disease, including any of the following:

  • NYHA class III or IV heart disease
  • Uncontrolled dysrhythmia
  • Myocardial infarction within the past 6 months

• No evidence of clinically active interstitial lung disease

  • Chronic stable radiographic changes that are asymptomatic allowed
• No evidence of any other severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease)
• No evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the trial

• No uncontrolled hypertension

  • Blood pressure must be ≤ 150/90 mmHg on a stable antihypertensive regimen

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 6 months since prior adjuvant chemotherapy
• No unresolved chronic toxicity > CTC grade 2 from prior anticancer therapy (except alopecia)
• More than 30 days since prior non-approved or investigational drugs
• No prior chemotherapy for advanced NSCLC
• No concurrent phenytoin, carbamazepine, rifampin, barbiturates, or St. John's wort
• No concurrent administration of other drugs known to inhibit EGFR
• No other concurrent anti-neoplastic or anti-tumor agents, including chemotherapy, radiotherapy, immunotherapy, or hormonal anticancer therapy
• No other concurrent investigational agents
• Concurrent cardioprotective doses of aspirin, as recommended by the physician, for cardiovascular disease allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment; Erlotinib followed by paclitaxel + carboplatin (+ bevacizumab in non-squamous) at the time disease progression.

Other: laboratory biomarker analysis; Blood and tissue collection.; Drug: bevacizumab; 15 mg/m2 given through a vein for every 3 weeks; Drug: carboplatin; AUC = 6 given through a vein on day 1 of each cycle.; Drug: erlotinib hydrochloride; 150 mg taken by mouth daily; Drug: paclitaxel; 200 mg/m2 given through a vein on day 1 of each cycle.; Genetic: gene expression analysis; Blood and tissue collection.; Genetic: protein expression analysis; Blood and tissue collection.; Genetic: proteomic profiling; Blood and tissue collection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pre-treatment Tumor Proteomic Profile as a Predictor of Response, Stable Disease, or Progressive Disease	End of treatment date

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pre-treatment Serum Proteomic Expression Pattern as a Predictor of Response to Erlotinib Hydrochloride and/or Carboplatin and Paclitaxel After Failing Treatment With Erlotinib Hydrochloride		End of treatment date
Tumor Proteomic Profiles as Predictors of Response to Carboplatin and Paclitaxel After Failing Treatment With Erlotinib Hydrochloride		End of treatment date
Analysis of Individual and Pattern(s) of Erlotinib Hydrochloride-induced Genomic and Proteomic Biomarker Changes in Relation to Response or Non-response to Treatment	End of treatment date	End of treatment date
Correlation of the Efficacy and Toxicity of Erlotinib Hydrochloride With Expression of EGFR, EGFR Pathway, ErbB Family, and Other Related Biomarkers		End of treatment date
Determination of a Set of Biomarkers to be Evaluated in Tumor Tissue or Surrogate Tissues Prior to Treatment With Erlotinib Hydrochloride to Enable Patient Selection for Therapy		End of treatment date
Response Rate for Erlotinib Initial Therapy in Chemotherapy-naïve Patients With Advanced NSCLC	Number of patients in each response category, per RECIST v1.1, summarized as follows for target lesion criteria (see RECIST v1.1 for additional details): complete response (CR),disappearance of target lesions; partial response (PR), >=30% decrease in sum of longest diameter of target lesions; progressive disease (PD), >=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or SD. The response rate is calculated as the percentage of PR+CR among patients assessed for response.	Through study completion, an average of 1 year
Progression-free Survival (PFS) for Erlotinib Initial Therapy in Chemotherapy-naïve Patients With Advanced NSCLC	PFS is defined as the time from on erlotinib treatment date to progression or death (whichever comes first) before cross-over to PC or PC+B. For those did not progressed nor died, they were censored at the last follow up (either the off erlotinib treatment date or lost follow up date). The median survival time and 95% confidence interval were estimated using Kaplan-meier method.	Through study completion, an average of 1 year
Number of Patients With Worst-grade Toxicities Per Grade	The intensity of the AE will be graded according to the Common Toxicity Criteria (CTC) of the (US) National Cancer Institute (NCI) - Cancer Therapy Evaluation Program (CTEP) [version 3.0 of December 2003] (Appendix B). Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE	Through study completion, an average of 1 year
Overall Survival for Erlotinib Initial Therapy in Chemotherapy-naïve Patients With Advanced NSCLC	The overall survival time is defined as the time from on treatment to death. Patients were censored of they were alive at the last follow up date. The median survival time and its confidence interval were estimated using Kaplan-meier method.	Through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Vanderbilt-Ingram Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: David Carbone, M.D., Ph.D., Vanderbilt-Ingram Cancer Center

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: October 26, 2007
• First Submitted That Met QC Criteria: October 26, 2007
• First Posted (Estimate): October 30, 2007

Study Record Updates

• Last Update Posted (Actual): June 8, 2017
• Last Update Submitted That Met QC Criteria: May 12, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: recurrent non-small cell lung cancer; stage IIIB non-small cell lung cancer; stage IV non-small cell lung cancer; squamous cell lung cancer; large cell lung cancer; adenocarcinoma of the lung; adenosquamous cell lung cancer; bronchoalveolar cell lung cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Carboplatin; Paclitaxel; Erlotinib Hydrochloride; Bevacizumab
• Other Study ID Numbers: VICC-THO-0640; P30CA068485 (U.S. NIH Grant/Contract); VU-VICC-THO-0640; VU-VICC-070494